Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure.
ABSTRACT Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage.
The aim of the present study was to compare cardiac sympathetic nervous activity assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure.
Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay.
Heart to mediastinum (H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001).
These data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.
Article: The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure.[show abstract] [hide abstract]
ABSTRACT: Because physicians have traditionally considered heart failure to be a hemodynamic disorder, they have described the syndrome of heart failure using hemodynamic concepts and have designed treatment strategies to correct the hemodynamic derangements of the disease. However, although hemodynamic abnormalities may explain the symptoms of heart failure, they are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient. Therapeutic interventions may improve the hemodynamic status of patients but adversely affect their long-term outcome. These findings have raised questions about the validity of the hemodynamic hypothesis and suggest that alternative mechanisms must play a primary role in advancing the disease process. Several lines of evidence suggest that neurohormonal mechanisms play a central role in the progression of heart failure. Activation of the sympathetic nervous system and renin-angiotensin system exerts a direct deleterious effect on the heart that is independent of the hemodynamic actions of these endogenous mechanisms. Therapeutic interventions that block the effects of these neurohormonal systems favorably alter the natural history of heart failure, and such benefits cannot be explained by the effect of these treatments on cardiac contractility and ejection fraction. Conversely, pharmacologic agents that adversely influence neurohormonal systems in heart failure may increase cardiovascular morbidity and mortality, even though they exert favorable hemodynamic effects. These observations support the formulation of a neurohormonal hypothesis of heart failure and provide the basis for the development of novel therapeutic strategies in the next decade.Journal of the American College of Cardiology 08/1992; 20(1):248-54. · 14.16 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.Journal of the American College of Cardiology 01/1995; 25(1):146-53. · 14.16 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Increased availability of norepinephrine (NE) for activation of cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of myocardial NE stores may contribute to the pathophysiology and progression of congestive heart failure. This study used a comprehensive neurochemical approach to examine the mechanisms responsible for these abnormalities. Subjects with and without congestive heart failure received intravenous infusions of [(3)H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic exchange, and tissue stores of NE were assessed from arterial and coronary venous plasma concentrations of endogenous and [(3)H]-labeled NE and dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma dopa, and NE turnover was assessed from measurements of NE metabolites. NE release and reuptake were both increased in the failing heart; however, the efficiency of NE reuptake was reduced such that cardiac spillover of NE was increased disproportionately more than neuronal release of NE. Cardiac NE stores were 47% lower and the rate of vesicular leakage of NE was 42% lower in the failing than in the normal heart. Cardiac spillover of dopa and NE turnover were increased similarly in congestive heart failure. Increased neuronal release of NE and decreased efficiency of NE reuptake both contribute to increased cardiac adrenergic drive in congestive heart failure. Decreased vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits the increase in cardiac NE turnover in CHF. Decreased NE store size in the failing heart appears to result not from insufficient tyrosine hydroxylation but from chronically increased NE turnover and reduced efficiency of NE reuptake and storage.Circulation 06/1996; 93(9):1667-76. · 14.74 Impact Factor
Vol. 19, No. 7, 2005
Annals of Nuclear Medicine Vol. 19, No. 7, 535–540, 2005
Received March 7, 2005, revision accepted June 15, 2005.
For reprint contact: Yasuchika Takeishi, M.D., First Depart-
ment of Internal Medicine, Yamagata University School of
Medicine, 2–2–2 Iida-Nishi, Yamagata 990–9585, JAPAN.
ACTIVATION of the sympathetic nervous system plays an
important role in the progression of congestive heart
failure.1–3 Iodine-123-metaiodobenzyl-guanidine (123I-
MIBG), an analogue of norepinephrine, has been devel-
oped and used to visualize cardiac sympathetic nervous
distribution and function.4–6 A number of studies have
reported that 123I-MIBG imaging provides powerful diag-
nostic and prognostic information in patients with heart
It has been reported that levels of multiple neurohu-
moral factors including norepinephrine and brain natri-
uretic peptide (BNP) are elevated in patients with heart
failure and related to the severity of the disease.14–16 On
the other hand, heart-type fatty acid binding protein (H-
FABP), a novel marker of ongoing myocardial damage, is
a small cytosolic protein that binds long chain fatty acid
and functions as the principle transporter of long chain
fatty acid in the cardiomyocyte.17–20 H-FABP is present
abundantly in the myocardium, and is released into the
circulation when the myocardium is injured. We have
recently demonstrated that the serum H-FABP level is
closely related to the severity of heart failure and predicts
Ongoing myocardial damage relates to cardiac sympathetic nervous
disintegrity in patients with heart failure
Takanori ARIMOTO, Yasuchika TAKEISHI, Takeshi NIIZEKI, Yo KOYAMA, Hidenobu OKUYAMA,
Naoki NOZAKI, Osamu HIRONO, Yuichi TSUNODA, Takehiko MIYASHITA, Tetsuro SHISHIDO,
Akio OKADA, Kazuei TAKAHASHI and Isao KUBOTA
First Department of Internal Medicine and Division of Radiology, Yamagata University School of Medicine
Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and
function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty
acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and
H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage.
Objective: The aim of the present study was to compare cardiac sympathetic nervous activity
assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure.
Methods: Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out
at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of
H-FABP using a sandwich enzyme linked immunosorbent assay. Results: Heart to mediastinum
(H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart
Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide
(BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was
significantly correlated with H-FABP (r = −0.296, p = 0.029) and BNP (r = −0.335, p = 0.0213).
Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001),
norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001). Conclusions: These data
suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte
damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-
MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic
nervous activity, but also latent ongoing myocardial damage in the failing heart.
Key words: H-FABP, 123I-MIBG imaging, heart failure
Annals of Nuclear Medicine
Takanori Arimoto, Yasuchika Takeishi, Takeshi Niizeki, et al
subsequent cardiac events independently of established
prognostic variables in chronic heart failure.20
Although several previous reports have identified that
123I-MIBG parameters are correlated with neurohumoral
factors such as norepinephrine and BNP,13,21–23 the rela-
tionship between cardiac sympathetic nervous activity
and myocardial cell injury remains to be elucidated.24 In
the present study, we examined whether sympathetic
nervous overactivity was accompanied by ongoing myo-
cardial damage in patients with chronic heart failure. We
compared parameters of 123I-MIBG imaging with the
serum level of H-FABP, a novel marker of cardiomyocyte
damage, in patients with heart failure.
We studied 50 patients (34 men and 16 women, mean age
of 65 ± 14 years) with heart failure who were admitted to
the Yamagata University Hospital. Written informed con-
sent was obtained from all patients, and the Institutional
Review Board on human research approved the study
protocol. Twenty-four age-matched normal subjects (17
men and 7 women, aged 64 ± 12 years) without heart
failure comprised the control group. The characteristics of
the patients are summarized in Table 1. The etiologies of
heart failure were ischemic heart failure in 10 (20%)
patients and non-ischemic heart failure in the remaining
40 (80%) patients. There were 26 patients with New York
Heart Association (NYHA) functional class II and 24
patients with class III. No patients had clinical symptoms
or signs suggestive of acute myocardial infarction, un-
stable angina, or acute myocarditis within the 3 months
preceding admission. Patients with renal insufficiency
determined by a serum creatinine level >1.5 mg/dl were
excluded from the present study.
A dose of 111 MBq of 123I-MIBG (Daiichi Radioisotope
Laboratories, Tokyo, Japan) was administered with 20 ml
saline under resting supine condition after an overnight
fast. All images were acquired using a three-head rotating
gamma camera equipped with a low-energy, high-resolu-
tion collimator (Multispect 3, Siemens Medical Systems,
Chicago IL, USA) as previously reported.25–27 Five min-
anterior planar imaging was carried out at 30 min and 240
min after the 123I-MIBG injection. The heart to mediasti-
num (H/M) rations of 123I-MIBG uptake at 30 min (early
H/M) and at 240 min (delayed H/M) were calculated (H:
mean counts/pixel in the left ventricular myocardium, M:
mean counts/pixel in the upper mediastinum) as previ-
ously reported.25–27 Washout rate from the myocardium
was calculated as [(H − M) at 30 min − (H − M) at 240 min]
× 100/(H − M) at 30 min (%).
Measurements of norepinephrine, BNP and H-FABP
A sample of venous blood was obtained from the study
population on the day of 123I-MIBG scintigraphy. Plasma
level of norepinephrine was measured with an automated
high-performance liquid chromatography analyzer (Tosoh
Co., Tokyo, Japan). We also measured the plasma level of
BNP by an immunoradiometric assay using a commer-
cially available kit (SHIONORIATM BNP, SHIONOGI
Co., Osaka, Japan). Serum H-FABP level was determined
by a sandwich enzyme linked immunosorbent assay using
two distinct murine anti-human H-FABP specific mono-
clonal antibodies (Markit-M H-FABP®, Dainippon Phar-
maceutical Co. Ltd., Tokyo, Japan). H-FABP in the test
sample was bound to a monoclonal anti-H-FABP anti-
body coated on microplate wells, and enzyme labeled
anti-H-FABP antibody was added to the wells to form a
sandwich immune complex.20 Substrate was added to
Table 1 Clinical background of patients with heart failure
(n = 50)
NYHA functional class (II/III)
Ischemic heart failure
Non-ischemic heart failure
Early H/M ratio
Delayed H/M ratio
Washout rate (%)
ACE inhibitors and/or ARBs
Ca channel blockers
65 ± 14
578 ± 368
504 ± 639
5.2 ± 3.3
52 ± 11
47 ± 21
1.81 ± 0.26
1.72 ± 0.28
42.9 ± 9.9
NYHA, New York Heart Association; BNP, brain natriuretic
peptide; H-FABP, heart-type fatty acid binding protein; LVEDD,
left ventricular dimension at end-diastole; LVEF, left ventricu-
lar ejection fraction; H, heart; M, mediastinum; ACE, angio-
tensin converting enzyme; ARB, angiotensin II receptor blocker.
Vol. 19, No. 7, 2005
start the enzymatic reaction, and absorbance was meas-
ured at 492 nm in a microplate reader.
Echocardiography was performed within 3 days after 123I-
MIBG scintigraphy using standard techniques. Left ven-
tricular dimensions at end-diastole and end-systole were
measured by two-dimensionally guided M-mode tracing,
and left ventricular ejection fraction was calculated based
on the Simpson’s rule.
All values were expressed as mean ± SD. Concentrations
of norepinephrine, BNP and H-FABP and parameters of
123I-MIBG imaging among NHYA functional classes
were compared by one-way ANOVA followed by a
Scheffe’s test. A p value less than 0.05 was considered
Norepinephrine, BNP and H-FABP levels in the study
Mean plasma levels of norepinephrine and BNP were 578
± 368 pg/ml (median 492, range 167 to 2,078) and 504 ±
639 pg/ml (median 201, range 20 to 2,540) in patients
with heart failure, respectively, as shown in Table 1. Mean
serum level of H-FABP was 5.2 ± 3.3 ng/ml (median
4.5, range 1.3 to 20). The relationships between levels
of these biochemical markers and the severity of heart
failure were examined in Figure 1. As reported in previ-
ous studies,14,15,20 levels of norepinephrine, BNP, and
Fig. 1 Levels of norepinephrine, BNP and H-FABP in study population.
Fig. 2 Parameters of 123I-MIBG imaging in study population.
Annals of Nuclear Medicine
Takanori Arimoto, Yasuchika Takeishi, Takeshi Niizeki, et al
H-FABP were significantly higher in heart failure patients
with NYHA class III than in control subjects. As the
severity of NYHA functional class advanced, norepi-
nephrine, BNP, and H-FABP levels increased (Fig. 1).
There were significant differences in BNP and H-FABP
levels between patients with NYHA class II and III.
H/M ratios and washout rate of 123I-MIBG in the study
Early and delayed H/M ratios were 1.81 ± 0.26 (median
1.75, range 1.27 to 2.35) and 1.72 ± 0.28 (median 1.72,
range 1.14 to 2.37), respectively, and washout rate was
42.9 ± 9.9% (median 42.8, range 21.2 to 61.1) in patients
with heart failure (Table 1). Correlations between 123I-
MIBG parameters and NYHA functional class were ex-
amined in Figure 2. As reported in previous studies, H/M
ratios of 123I-MIBG at early and delayed images were
lower in patients with NYHA class III than in control
subjects. Washout rate of 123I-MIBG was faster in patients
with NYHA class II and III compared to control subjects.
H/M ratios decreased, whereas washout rate increased
with advancing of NYHA functional class (Fig. 2).
Correlations between biochemical markers and 123I-MIBG
We compared levels of biochemical markers with 123I-
MIBG parameters. There was a weak but statistically
significant correlation between serum H-FABP levels and
delayed H/M ratio of 123I-MIBG (r = −0.296, p = 0.029)
as shown in Figure 3. Serum H-FABP levels were also
correlated significantly with the washout rate of 123I-
MIBG from the myocardium (r = 0.469, p < 0.001). These
data indicated that high H-FABP levels were accompa-
nied by high cardiac sympathetic nervous activity.
In accordance with previous reports,21,22 plasma levels
of norepinephrine were correlated with the washout rate
of 123I-MIBG from the myocardium (r = 0.433, p =
0.0052). Plasma BNP levels were also correlated with
delayed H/M ratio (r = −0.335, p = 0.0213) and washout
rate (r = 0.465, p = 0.001) of 123I-MIBG. Early H/M ratio
did not correlate with any markers in the present study.
In the present study, we demonstrated that serum levels of
H-FABP, a new marker of cardiomyocyte injury, were
increased in patients with heart failure. H-FABP levels
were correlated significantly with H-M ratio at delayed
images and washout rate of 123I-MIBG, indicating that the
ongoing cardiomyocyte damage related to cardiac sym-
pathetic nervous disintegrity in patients with heart failure.
Assessing cardiac autonomic status is clinically impor-
tant in the management of patients with heart failure, since
sympathetic nervous activation causes excessive ven-
tricular afterload, down-regulation of β-adrenergic recep-
tors, tachycardiac interference with ventricular filling,
heart failure progression, and increased mortality.28
Elevated circulating norepinephrine levels, reflecting
increased sympathetic nervous system activity, are an
indirect marker for mortality related to severe heart fail-
ure.14 A different approach for measuring sympathetic
nervous function in the heart is to evaluate the capacity of
cardiac sympathetic nerve terminals to take up catechola-
mines by the uptake-1 transporter. This assessment can be
made non-invasively using 123I-MIBG and such imaging
allows the evaluation of sympathetic tone in the clinical
setting.4–6 As shown in Figures 1 and 2, neurohumoral
factors and 123I-MIBG parameters were correlated with
the severity of heart failure in accordance with previous
During the development of cardiac hypertrophy and
transition to heart failure, a switching of energy substrate
utilization occurs with reduced fatty acid oxidation and
increased glucose utilization.29–31 H-FABP plays a criti-
cal role in the uptake and transport of long chain fatty acid
in the cardiomyocyte. Both cellular uptake and lipid
oxidation of long chain fatty acids are severely depressed
in H-FABP knockout mice.32 On the other hand, H-FABP
is rapidly leaked into the circulation when the myocar-
dium is injured. In this regard, H-FABP has been recently
used as a biochemical marker for acute myocardial infarc-
tion17–19 and also a clinical marker to reflect ongoing
myocardial damage in patients with severe heart failure.20
Fig. 3 Correlations between parameters of 123I-MIBG imaging and serum levels of H-FABP.
Vol. 19, No. 7, 2005
Our study suggested that while levels vary directly with
severity, H-FABP was released from the damaged myo-
cardium at each stage of heart failure (Fig. 1).
Although several parameters of 123I-MIBG imaging
provide promising information to assess patients with
heart failure,7–13 the precise mechanism that underlies
these findings has not yet been established. We found a
correlation between serum level of H-FABP, a new marker
of myocardial damage, and parameters of 123I-MIBG
imaging. Sustained sympathetic nervous overactivity
causes excess norepinephrine release from the presynap-
tic nerve terminal endings, resulting in norepinephrine
depletion and downregulation of β-adrenergic receptors
in the myocardium.1–3 These changes are also associated
with histopathologic abnormalities, such as myocyte de-
generation and necrosis in response to increased sympa-
thetic nervous activity.33 Indeed in the present study,
serum H-FABP level was correlated significantly with H/
M ratio at delayed images and washout rate of 123I-MIBG,
which may reflect, at least in part, enhanced norepineph-
rine release from the presynaptic nerve terminal endings,
increased norepinephrine spillover, and decreased up-
Serum levels of H-FABP were augmented in some
patients with high delayed H/M ratio. Although we ex-
cluded the patients with serum creatinine level >1.5 mg/
dl, even a slight decrease in renal function might influence
the serum level of H-FABP. On the other hand, low serum
H-FABP levels were observed in some patients with low
delayed H/M ratio of 123I-MIBG. In this case, it is possible
that ongoing myocardial damage might be delayed after
cardiac sympathetic nervous dysfunction.
The percentage of patients who had taken β-blockers,
ACE inhibitors and/or ARBs was relatively low in the
present study. However, this study included mild to mod-
erate heart failure patients with non-ischemic etiologies
and patients with preserved left ventricular systolic func-
tion. We started β-blockers, ACE inhibitors and/or ARBs
in almost all patients after 123I-MIBG imaging.
H-FABP is released into the circulation from the dam-
aged myocardium, whereas BNP is secreted in response
to mechanical overload to the ventricles.34,35 These differ-
ences may support the rationale of combined use of these
factors for risk stratification of patients with heart failure.
Kyuma et al. showed that delayed H/M ratio of 123I-MIBG
and plasma BNP level enable better stratification of heart
failure patients at augmented risk for cardiac events.23
Additionally, we have recently shown that combined
measurements of serum H-FABP and plasma BNP levels
are helpful to monitor disease outcome in patients with
heart failure.36 In future research, we need to examine
whether the combined assessment of cardiac sympathetic
nervous activity, myocardial cell injury and other bio-
chemical markers would effectively risk stratify patients
with heart failure.
We demonstrated in the present study that activation of
the cardiac sympathetic nervous system was associated
with ongoing cardiomyocyte damage characterized by an
elevated serum level of H-FABP in heart failure patients.
123I-MIBG imaging may be useful for evaluating not only
cardiac sympathetic nervous activity, but also latent myo-
cardial damage in the failing heart.
This study was supported in part by a grant-in-aid for Scientific
Research (No. 17590702) from the Ministry of Education,
Science, Sports and Culture, Japan and grants from The Mochida
Memorial Foundation and Takeda Science Foundation.
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